B116 Degenerative diseases and dementias

Question 1

General characteristic of degenerative diseases

Answer 1

Progressive neuronal degeneration, decline of brain function.

Dementia, memory impariment and cognitive deficits with a normal level of consciousness.

Question 2

Alzheimer’s

Answer 2

Progressive dementia, memory loss, aphasia

95% are sporadic, 5% familial early onset.

Accumulation of beta amyloid plaques, derived APP

APP is cleaved without amyloid production by the alpha-secretase or gamma-secretase pathway

Abeta is generated by beta-site cleaving enzyme and gamma secretase

APP is found on chromosome 21, and alzheimers is increased in Downs.

Specific ApoE4 allele is found in 30% of cases.

Amyloid pathogenesis:

• Small aggregates alter neurotransmission and can damage synapses
• Large deposit, plaques: induce local inflammation and neuronal injury, death.
• hippocampal CA1
• Entorhinal cortex
• Chonlinergic forebrain nuclei.
• On gross specimen, atrophy is prominent in the frontal and parietal lobes (wide sulci, narrow atrophied gyri), with the occipital lobe mostly spared

Question 3

Parkinsons cause and symptoms

Answer 3

Unknown cause of death of the dopaminergic cells of the substantia nigra. Neuronal death also occurs in the locus coeruleus norepinerphine neurons. Primary PD is the most common, but it can also be caused by drugs that affect these neuronsor other diseases: Post encephalitic parkinsonism after some flu epidemics, some Huntinton cases, some other CNS degenerative conditions.

Symptoms:

Motor symptoms

• resting tremor is the most common, dissapears on voluntary movement and sleep
• cogwheel rigidity and difficultly initiating movement,
• bradykinesia, slow movement
• difficulty halting movement
• rigidity
• postural instability, falls
• shuffling gait
• masked face, lack of facial expression
• speech difficulty
• dysphagia
• fatigue

Cognitive

• progressive deterioration of cognititon
• progressive dementia
• depression
• anxiety

Question 4

Parkinson’s key histology

Answer 4

Diagnostic feature is the Lewy body intracellular inclusions of alpha-synuclein in neurons. Suggesting defective degradation

alpha synuclein is widely expressed in neurons and involved in synaptic transmission

Question 5

Parkinson’s treatment

Answer 5

L-Dopa administration is very effective at treating symptoms for a period of time.

Does not slow or later disease progression. Over 10-15 years the disease progresses to eventual paralysis and death.

Has some major side effects,

• immunity can develop
• can iduce its own L-Dopa induced dyskinesia.
• psychiatric, hallucinations
• sleep disturbances

Anticholinergics can also suppress tremor

Deep brain stimulationL to the thalamus, subthalamic nucleus, or globus pallidus.

DBS, and L DOPA can be very effective at controlling symptoms.

Question 6

Huntington disease pathogenesis

Answer 6

An inherited disease. Caused by CAG repeats in the gene for Huntingtin protein. normally 10-35 repeats. Disease is caused on expansion, and severity increases with repeats, early onset is associated with greater than 70 copies, can get to be hundreds.

Unclear mechanism, but likely due to sequestration of other proteins that bind to these repeats, especially transcription factors. As well as misfolding and loss of function of the huntingtin protein itself.

Mitochondrial dysfunction also seems to be involved.

There is general neuronal degeneration throughout the brain

Earliest changes: In the striatum

Other involved areas: Subs. nigra, cortical pyramidal neurons, purkinje cells, hippocampus, hypothalamus and thalamus

Question 7

Huntington’s presentation and symptoms

Answer 7

Symptoms appear in the 30’s and 40’s, but onset varies with degree of repeat expansion.

Can appear very early, in teenagers or children.

Motor symptosm appear first:

• choreiform dyskinesia, Huntington’s chorea

Followed by cognitive decline:

• fogetfulness, memory loss
• emotional, behavioral changes
• progresses to severe dementia

Question 8

Amyotrophic lateral sclerosis pathogenesis

Answer 8

Degeneration of the ventral horn motor neurons of the spinal cord and upper motor neurons of the CNS.

Sporadic, idiopathic cases and familial cases.

50% of familial cases have gain-of-function mutations to the Superoxide dismutase gene SOD1, on chromosome 21. These act as dominant mutations only requiring one mutant allele.

Involved in oxidative stress, mitochondrial damage, and apoptosis pathways.

Question 9

ALS symptoms, progression, treatment

Answer 9

Causes symptoms based on loss of both of these neuron groups:

The symptoms are often assymetric. Cognition and mental abilites are usually not affected, although uncommly dementia may also occur

Early signs:

• hand weakness, dropping things and difficulty with fine motor tasks
• cramping and spasticity of the arms and legs
• stiffness, fasciculations/contractures of the arms and legs

Late symptoms/mortality

• eventual paralysis
• death from respiratory insufficiency and secondary pulmonary infections.

i. Loss of the projection of upper motor neurons onto the lower motor neurons

• Paresis
• Hyperreflexia
• Spasticity
• Positive Babinski sign.

ii. Loss of lower motor neurons

• Denervation of muscular targets with symptoms of muscular atrophy
• Weakness, flaccid paralysis
• Fasciculations.